Currently, it is said that the disease known as fibrosis includes 130 types or more of diseases, if rare diseases are also included therein. Representative examples of such fibrosis include lung fibrosis, hepatic fibrosis, and glomerulosclerosis.
In general, lung fibrosis refers to a group of diseases associated with loss of lung functions due to a lesion regarding the reconstruction of an alveolar region, which is caused by the phenomenon whereby the alveolar structure is destroyed by an inflammatory reaction, and as a result, growth of fibroblasts and an excessive increase in extracellular matrix mainly composed of collagen take place, so that the lung becomes hardened.
Moreover, hepatic fibrosis refers to a pathologic condition associated with fibrosis of the liver, which is caused by the phenomenon whereby hepatic cells are necrotized by various types of hepatopathy such as chronic viral hepatitis or alcoholic hepatitis, and thereafter, extracellular matrix increases to replenish the necrotized portion, resulting in such fibrosis of the liver. This pathologic condition finally leads to hepatic cirrhosis, in which the entire hepatic fibers shrink and become hardened.
In order to suppress the aforementioned hepatic fibrosis, drugs such as Penicillamine or Lufironil have been used. Penicillamine has been known as a drug for treating Wilkinson's disease that is developed as a result of accumulation of copper in the liver due to abnormality of copper metabolism. Lufironil has been studied for its use as a proline hydroxylase inhibitor.
However, taking into consideration their side effects and effectiveness, the aforementioned drugs do not sufficiently function as drugs for preventing fibrosis of the liver. Thus, as a matter of fact, neither therapeutic agents nor methods for treating fibrosis, which are effective for fibrosis, including hepatic fibrosis as a representative example, have been established to date. A method of specifically inhibiting a process of developing fibrosis has become a focus of attention in the research field.
As stated above, it has been known that an excessive increase in extracellular matrix mainly composed of collagen takes place during a process of development of fibrosis in the lung tissues or hepatic tissues. Moreover, it has also been known that such an increase in extracellular matrix in hepatic cells takes place mainly in sinusoidal wall Disse's space, and that Ito cells that are mesenchymal cells in the liver are main sources for production of such extracellular matrix.
Accordingly, in order to suppress fibrosis occurring in the liver, the lung, or other organs, it is important to suppress an excessive increase in extracellular matrix (namely, collagen).
JP-A-2002507601 and JP-A-200189450 disclose that a certain type of pyridine derivative has an effect of suppressing the production of collagen and thus is effective for fibrosis. JP-A-200189412 discloses that a certain type of benzene derivative has an effect of suppressing the production of collagen and thus is effective for fibrosis. However, there still remains a demand for a development of a compound that exhibits a better effects in suppressing the production of collagen with little side effect in a high safely manner.
In 1940s, nitrogen mustard was clinically used as an anticancer drug for the first time in the world. Since then, various anticancer drugs have been developed in the field of cancer treatment. For example, 5-fluorouracil and like antimetabolites, adriamycin and like antitumor antibiotics, cisplatin and like platinum complexes, vindesine and like plant origin anticancer agents, etc., are actually used.
However, these anticancer agents also exhibit cytotoxicity towards healthy cells and often result in digestive system disorders, bone marrow depression, hair loss and similar critical side effects. Due to these side effects, their usage is limited and their therapeutic effect itself is often effective only partially and in a short term.
Although various attempts have been made to develop novel anticancer agents which can take place these known anticancer agents, there are no satisfactory results obtained so far.